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Ann Thorac Surg 1997;63:449-454
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Functional and Metabolic Effects of Adenosine in Cardioplegia: Role of Temperature and Concentration

Heart Science Centre, National Heart and Lung Institute at Harefield Hospital, Harefield, Middlesex, United Kingdom

Accepted for publication August 31, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Addition of adenosine to cardioplegic fluid has been shown to improve myocardial tolerance to ischemia. This study was designed to investigate further this phenomenon to evaluate the dose-response and the temperature dependence of the effect of addition of adenosine to St. Thomas' Hospital cardioplegic solution.

Methods. The isolated working rat heart model was used in this study. After the assessment of control function, hearts (6 in each group) were subjected to infusions of cardioplegic solution containing 0.0 (control), 0.1, 5.0, 10.0 or 20.0 mmol/L adenosine followed by 3 hours of ischemic arrest at temperatures of 20°C, 10°C, or 4°C with multidose (3 minutes every 30 minutes) cardioplegic infusion.

Results. After ischemic arrest at 20°C, the recovery of cardiac output (expressed as percent of preischemic baseline) was 35.4 ± 5.11 (control) 45.0 ± 5.51 (0.1 mmol/L), 53.1 ± 2.9 (5.0 mmol/L), 61.8 ± 3.7 (10.0 mmol/L), and 57.6 ± 2.3 (20.0 mmol/L). Hearts receiving 5.0 to 20.0 mmol/L adenosine had significantly greater recovery of cardiac output than control hearts. In its optimal concentration (10 mmol/L), adenosine improved the efficacy of the cardioplegic solution by almost 75%. Myocardial adenosine triphosphate content (expressed in µmol/g protein) was 4.7 ± 0.5 (control), 4.9 ± 1.4 (0.1 mmol/L), 8.1 ± 0.7 (5 mmol/L), 12.5 ± 2.0 (10 mmol/L), and 11.2 ± 2.8 (20 mmol/L), at the end of ischemia and 13.9 ± 0.2 (control), 13.1 ± 1.7 (0.1 mmol/L), 18.0 ± 2.0 (5 mmol/L), 18.6 ± 1.2 (10 mmol/L), and 20.7 ± 2.1 (20 mmol/L) at the end of reperfusion. Thus, the adenosine triphosphate content was higher (p < 0.05) in hearts receiving 5.0 to 20.0 mmol/L adenosine than in controls both at the end of ischemia and after reperfusion. Myocardial adenosine monophosphate level at the end of ischemia was inversely related to adenosine triphosphate level. Functional assessment of the effect of 10 mmol/L adenosine at 10°C and 4°C during arrest indicated attenuation of beneficial effects: adenosine improved function only by 17% at 10°C, whereas at 4°C the protective effect was not observed.

Conclusions. These observations suggest that adenosine has the potential to enhance the efficacy of clinical cardioplegic arrest but the degree of improvement is lower at decreased temperature during ischemia. A principal mechanism of action of this modification of cardioplegic fluid appears to be through the inhibition of high-energy phosphate utilization immediately before or during ischemia.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 454.

Adenosine expresses numerous pharmacologic properties that render it useful for the protection of the ischemic myocardium [1]. Endogenous adenosine is formed predominantly in myocardial cells from the degradation of adenosine triphospate (ATP) and its release into the interstitial space, particularly during ischemia [2]. Exogenous adenosine has been shown to improve the function, viability, and metabolism when given as cardioplegic constituent or applied during reperfusion [3–5]. We have previously reported the beneficial effects of low-dose exogenous adenosine on postischemic functional recovery, when it was used to increase coronary flow during reperfusion after hypothermic cardioplegic arrest [6, 7]. Because most of the evidence in favor of the beneficial effects of exogenous adenosine has been gathered at normothermia or without cardioplegic protection, we considered it was important to undertake studies designed to evaluate the benefit of adenosine supplement of multidose hypothermic cardioplegic arrest. We defined its dose-response and temperature dependence by evaluation of the effects of adenosine on mechanical function and myocardial nucleotide metabolism.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experimental Preparation
Hearts were obtained from male rats, weighing between 250 and 300 g, of the Spague-Dawley strain. The animals were anesthetized with halothane, which had been mixed with 95% oxygen plus 5% carbon dioxide. The femoral vein was then exposed and heparin (200 IU) was injected. One minute later the heart was excised and immediately placed into cold (0°C) perfusion fluid. Approximately 30 seconds later, the aorta was cannulated and Langendorff perfusion at 37°C was initiated for a 3-minute washout period. During this time the left atrium was cannulated and an incision was made in the pulmonary artery to ensure the ejection of coronary effluent. The working rat heart model has been described in detail previously [4]. Briefly, after cannulation of the aorta and left atrium, perfusion fluid can be either pumped around the circuit in the working mode or perfused into the aortic root in the nonworking, Langendorff mode. Cardioplegic arrest was induced by clamping the aortic and atrial cannulas and infusing cardioplegic solution into a sidearm of the aortic cannula from a height of 60 cm. Water-jacketed chambers maintained the heart under either normothermic or hypothermic conditions. Myocardial temperature was measured regularly both during normothermic and hypothermic conditions using a thermocouple-type thermometer inside the heart; the temperature was maintained within ±0.5°C of the preset value.

Cardioplegic Solution
The solution used was the commercially available form of St. Thomas' Hospital cardioplegic solution No. 1. It was supplied as a concentrate (David Bull Laboratories, Mulgrave, Victoria, Australia), which was diluted in a 1-L bag of Ringer's solution (Travenol Laboratories Ltd, Thetford, Norfolk, England) before use. The final composition was as follows: NaCl, 144.0 mmol/L; KCl, 20.0 mmol/L; MgCl, 16.0 mmol/L; CaCl, 2.2 mmol/L; procaine hydrochloride, 1.0 mmol/L; osmolarity, 300 to 320 mOsm/kg H₂O; and pH, 5.5 to 5.7. The solution was used directly from the bag, but before infusion was passed through a Pall 0.2-µm cardioplegic filter (Pall Biomedical Ltd, Glen Cove, NY) to remove any particulate contaminants.

Adenosine
Adenosine (Sigma Chemical Co Ltd, Poole, Dorset, England) was added to the bags of cardioplegic solution to bring the concentrations of adenosine in the solution to 0.1, 5.0, 10.0, and 20.0 mmol/L. Because adenosine at higher concentrations was difficult to dissolve in the cardioplegic solution, the bags were warmed in a water bath at 37°C. Subsequent cooling of the bags to 4°C does not lead to recrystallization.

Experimental Protocol
After initial Langendorff perfusion, hearts were switched into working mode for 20 minutes. During this time, control values for heart rate, peak aortic pressure, instantaneous differentiation of pressure (dP/dt), and aortic and coronary flow rates were recorded. Any heart that did not achieve a steady level of function with a cardiac output (aortic plus coronary flow) greater than 85 mL/min was rejected. At the end of the control period, the atrial and aortic cannulas were clamped and the heart was immediately subjected to a 3-minute hypothermic infusion with one of the solutions under study, at either 20°C, 10°C, or 4°C. The volume of solution infused was recorded to determine coronary flow. The heart was then maintained in a state of hypothermic ischemic arrest, immersed in the same solution under study, for 3 hours at 20°C or 4 hours at 10°C and 4°C, with cardioplegic reinfusions for 3 minutes every 30 minutes. The volume of solution infused during the last reinfusion before reperfusion was again recorded to determine coronary flow at this time. At the end of the ischemic period each heart was reperfused at 37°C, initially in the Langendorff mode for 15 minutes and then converted to the working mode for a further 20 minutes. During this last period the reperfusion values for heart rate, peak aortic pressure, dP/dt, and aortic and coronary flow rates were recorded. In experiments performed at 20°C, adenosine was added in increasing concentrations to the cardioplegic solution or omitted in the control group in a randomized fashion. In experiments performed at 10°C and 4°C, 10 mmol/L adenosine was added to the cardioplegic solution or omitted in the control group in a randomized fashion. Six hearts were studied in each group.

Metabolic Studies
Metabolic determinations were performed in groups of hearts subjected to cardioplegic arrest at 20°C. All hearts in the functional studies were freeze-clamped at the end of the working period. In addition, in a parallel series of experiments, groups of hearts were freeze-clamped at the end of the period of cardioplegic arrest without reperfusion. Hearts were stored in liquid nitrogen until a 100-mg sample from each heart was submitted to the process of extraction and determination of nucleotide and nucleoside content by high-performance liquid chromatography using the reversed-phase method described in detail previously [8]. Protein content was evaluated in perchloric acid precipitates according to the Lowry method [9]. The information obtained included concentrations of myocardial nucleotide and nucleosides and bases at the end of ischemia and at the end of reperfusion for each concentration of adenosine studied.

Expression of Results
The volume of cardioplegic solution infused during the first and last 3-minute administrations was recorded and used to calculate the coronary flow rate in milliliters per minute at these times. At the end of the preischemic and postischemic working periods the following indices of mechanical function were recorded: heart rate, peak aortic pressure dP/dt, aortic flow, and coronary flow. Cardiac output was derived from the sum of aortic and coronary flows. Postischemic recovery values of mechanical function were then expressed as a percentage of their individual preischemic control values. Nucleotide and nucleoside content of hearts freeze-clamped at the end of ischemia or at the end of reperfusion were expressed in micromoles per gram of protein. Statistical analysis of differences between groups was performed using one-way analysis of variance followed by Student-Newmann-Keuls test, and significance was assumed when the p value was 0.05 or less.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Coronary Flow During Cardioplegia Infusion
The mean coronary flow rates during the first and last infusions of cardioplegic fluid are shown in Figure 1. In comparison with the control group, coronary flow was increased in the group receiving 10 mmol/L adenosine by approximately 25% during both the first and last cardioplegic infusions, whereas no significant differences were observed in the other groups.

View larger version (47K): [in this window] [in a new window]   Fig 1. . Coronary flow during the first and the last infusion of cardioplegic solution containing different concentration of adenosine. Values are the means ± standard error of the mean. (*p < 0.05 versus 0 mmol/L adenosine; **p < 0.05 versus 0 and 0.1 mmol/L adenosine.)

View larger version (61K): [in this window] [in a new window]   Fig 2. . Recovery of functional parameters after cardioplegic arrest and ischemia with cardioplegic solution containing different concentration of adenosine. Values are the means ± standard error of the mean. (AF = aortic flow; CF = coronary flow; CO = cardiac output; dP/dt = first derivative of pressure; PAP = peak aortic pressure; *p < 0.05 versus 0 mmol/L adenosine; **p < 0.05 versus 0 and 0.1 mmol/L adenosine.)

View larger version (19K): [in this window] [in a new window]   Fig 3. . Recovery of cardiac output after ischemia at different temperatures with adenosine concentration of 0 or 10 mmol/L. Values are the means ± standard error of the mean. (*p < 0.05; **p < 0.01.)

Metabolic Status
The mean concentrations of myocardial ATP, adenosine diphosphate (ADP), adenosine monophosphate (AMP), inosine, hypoxanthine, and adenosine at the end of ischemia and at the end of reperfusion are shown in Figure 4. At the end of ischemia ATP and ADP concentrations were higher in hearts receiving 5 mmol/L or greater concentrations of adenosine compared with the control group. Moreover, the content of AMP was lower and the contents of inosine and hypoxanthine were higher in the groups receiving adenosine. Adenosine content in the heart at the end of ischemia was 1.7 ± 0.3, 2.4 ± 0.4, 20.7 ± 1.7, 30.4 ± 2.4, and 70.8 ± 5.4 µmol/g protein in the 0, 0.1, 5, 10, and 20 mmol/L adenosine groups, respectively. At the end of reperfusion considerable recovery of ATP had taken place in the control and 0.1 mmol/L groups, but at 5.0 mmol/L or greater concentrations of adenosine this recovery was higher, reaching statistical significance in the 10 and 20 mmol/L groups. At this time the content of ATP was elevated in the 20 mmol/L adenosine group, but ADP, AMP, adenosine, inosine, and hypoxanthine levels were similar in all groups (Fig. 5).

View larger version (47K): [in this window] [in a new window]   Fig 4. . Concentrations of adenosine triphosphate (ATP) and related metabolites in the heart at the end of ischemia in hearts infused with cardioplegic solution containing different concentrations of adenosine. Values are the means ± standard error of the mean. (ADP = adenosine diphosphate; AMP = adenosine monophosphate; HYP = hypoxanthine; INO = inosine; *p < 0.05 versus 0 mmol/L adenosine; **p < 0.05 versus 0.1 mmol/L adenosine; #p < 0.05 versus 5 mmol/L adenosine and p < 0.05 versus 10 mmol/L adenosine.)

View larger version (24K): [in this window] [in a new window]   Fig 5. . Concentrations of adenosine triphosphate (ATP) and related metabolites in the heart after reperfusion. Hearts were infused with cardioplegic solution containing different concentrations of adenosine. Values are the means ± standard error of the mean. (*p < 0.05 versus 0 mmol/L adenosine; **p < 0.05 versus 0.1 mmol/L adenosine; abbreviations are as in Figure 4.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Effects of Adenosine on Nucleotide Metabolism and Mechanical Function
In the ischemic myocyte ATP is dephosphorylated to ADP, to AMP, and further to adenosine or alternatively to inosine monophosphate and inosine. Nucleosides can then be released from the myocytes into the interstitial space and taken up by the endothelial cells, via membrane transport mechanisms, where they can then be progressively metabolized to inosine, hypoxanthine, xanthine, and uric acid [10–13]. Adenosine is also the most effective substrate for adenine nucleotide resynthesis [14], but due to washout with blood or cardioplegic fluid, endogenously produced adenosine can be utilized only by the endothelial cells. When exogenous adenosine is applied, the coronary endothelium acts as an impermeable metabolic barrier up to concentrations not greater than 1 µmol/L [15]. Above that level adenosine can be also taken up by the myocytes and incorporated into ATP. Uptake of adenosine into the cell involves a saturable temperature-dependent transport system (much more effective in endothelium) [11, 16]. At concentrations greater than 100 µmol/L adenosine enters the cell predominantly by passive diffusion. Inside the cell, adenosine is rapidly phosphorylated to AMP via adenosine kinase. However, kinetic characteristics of this enzyme include a substrate-inhibition effect at concentrations above 30 µmol/L [14, 17]. Consequently, maximal incorporation of adenosine into the nucleotide pool occurs at 20 to 30 µmol/L concentrations and decreases above that level. At higher concentrations of adenosine, deamination of this nucleoside becomes the preferential pathway. This was observed also in this study, where high concentrations of exogenous adenosine were associated with accumulation of inosine and hypoxanthine. We also observed that the content of AMP was significantly lower and the contents of inosine and hypoxanthine were significantly higher at the end of ischemia in the groups receiving 5 mmol/L or greater concentrations of adenosine are able to suppress utilization of ATP during ischemia. Although depressed ATP level is used as a criterion of the likelihood of functional recovery and severe depletion is associated with poor recovery, moderate depletion has not been shown to correlate with the degree of functional impairment. In the present studies, enhanced functional recoveries in hearts receiving adenosine were associated with enhanced preservation of ATP during ischemia and enhanced recovery of ATP at the end of reperfusion. Adenosine triphosphate content at the end of reperfusion was limited by the availability of AMP and ADP at the end of ischemia. Rapid washout of purine precursors at reperfusion did not provide substrates for nucleotide synthesis.

Adenosine, through its action on adenosine A₁ receptors, has been demonstrated to increase the potassium permeability of atrial and sinus node tissues such that there is an outward potassium flux, which hyperpolarizes the membrane potential and causes both inhibition of atrial activity and atrioventricular block [18, 19]. This could be responsible for more rapid arrest of ventricular contraction than potassium alone [20], finally resulting in reduction of ATP utilization in the heart. The cardioprotective effect of preconditioning were found to be also mediated by A₁ receptor activation, and similar mechanisms could be induced by addition of adenosine into the cardioplegic fluid [21].

The present findings are in agreement with most of the recent reports on the addition of adenosine to cardioplegic solutions. In an in vivo, isovolumic preparation in dogs undergoing 1 hour of normothermic ischemia, the addition of adenosine (100 µmol/L), hypoxanthine (100 µmol/L), and ribose (2 mmol/L) to a crystalloid cardioplegic solution resulted in improved functional recovery [22]. In agreement with the present study, the authors of that study observed a significant correlation between ATP level at the end of ischemia and at the end of reperfusion with functional recovery, and also noted that the rate of recovery of ATP was not influenced by nucleoside augmentation. In an isovolumic preparation in rabbits undergoing 2 hours of mildly hypothermic (32°C) multidose cardioplegic arrest, adenosine was added to the cardioplegic solution in concentrations of 100, 200, and 400 µmol/L [23]. There was a significant incremental increase in functional recovery with increasing doses of adenosine, with a maximal effect at 200 µmol/L, but no metabolic studies were performed. In a subsequent report [24], with a similar protocol at 34°C, the same investigators compared the effects of adenosine (200 µmol/L) with those of 2-deoxycoformycin (an inhibitor of adenosine deaminase), and with a combination of both against controls. It was claimed that there was better diastolic function during postischemic isovolumic contraction in the adenosine-augmented groups. Parallel metabolic studies revealed that augmenting myocardial adenosine, in contrast to the present study, had no effect on depletion of ATP during ischemia, but significantly increased the recovery of ATP during reperfusion in the group receiving adenosine alone, such that at the end of 15 minutes of reperfusion the level of ATP was significantly greater than its preischemic control value. The improved functional recovery was claimed, at least in part, to be due to accelerated postischemic repletion of ATP, presumably from a better maintained nucleoside pool, but there was no analysis of nucleoside levels. Interestingly, the investigators noted that intramyocardial pH during ischemia was better maintained in the adenosine-augmented hearts. Another recent study demonstrated, in contrast to the present report, that a low dose of adenosine (0.05 mmol/L) added to cardioplegic fluid was more effective than a high dose (5 mmol/L) in improving mechanical function [25]. The most important difference between this report and our studies is that the temperature during ischemia was 37°C. In view of our data on strong temperature dependence of adenosine effects, this could be sufficient reason to explain this difference. It should be pointed out that our data are more relevant to clinical situations.

Effect of Adenosine on Flow During Cardioplegic Infusion
In our earlier study demonstrating the beneficial effects of low-dose adenosine during reperfusion after hypothermic cardioplegic arrest, 3.75 µmol/L adenosine increased mean coronary flow by more than 50% [7]. In contrast, in the present study 100 µmol/L adenosine had no effect on coronary flow during cardioplegic infusion, and only 5 mmol/L and greater concentrations increased it by about 25%. Thus, it is possible that the moderately increased volumes and potentially improved distribution of cardioplegia in the hearts receiving 5 mmol/L or greater concentrations of adenosine may have contributed to the enhanced myocardial preservation seen in these groups.

Importance of Temperature for Adenosine Effect
Comparing results of the studies performed at normothermia and our data at different temperatures, it is clear that this factor greatly affects the role of adenosine in cardioplegic fluid. The protective effect of this modification seems to disappear with decreasing temperature. If a decrease in ATP utilization is the mechanism of adenosine's effect, it is possible that under deep hypothermic conditions when preservation of ATP is excellent [26] there will be no potential for further improvement. It could be thus concluded that modification of cardioplegic fluid with adenosine may exert the strongest effect during routine cardiac operations applying usually moderate hypothermia, whereas it could be less effective during heart transplantation when the heart is maintained under deep hypothermic conditions.

Conclusions
The present studies have demonstrated that adenosine has the potential to enhance the efficacy of multidose cardioplegic arrest, when added to a commonly used cardioplegic solution. However, the degree of additional protection was inversely related to the temperature, and at deep (4°C) hypothermia no improvement was observed. The optimal adenosine concentration for maximum postischemic functional recovery was 10 mmol/L. The mechanism by which adenosine appears to achieve this effect is through the inhibition of ATP utilization. It is possible that other properties of adenosine, including coronary vasodilatation and inhibition of myocardial excitation, may have played an additional role.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by the Harefield Heart Transplant Trust and the British Heart Foundation.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Prof Yacoub, Heart Science Centre, National Heart and Lung Institute at Harefield Hospital, Harefield, Middlesex UB9 6JH, UK.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989;32:73–97.[Medline]
2. Berne RM. The role of adenosine in the regulation of coronary blood flow. Circ Res 1980;47:807–13.[Free Full Text]
3. Ely SW, Berne RM. Protective effects of adenosine in myocardial ischemia. Circulation 1992;85:893–904.[Abstract/Free Full Text]
4. Ledingham SJ, Katayama O, Lachno DR, Yacoub M. Prolonged cardiac preservation. Evaluation of the University of Wisconsin preservation solution by comparison with the St. Thomas' Hospital cardioplegic solutions in the rat. Circulation 1990;82(Suppl 4):351–8.
5. De Jong JW, Van der Meer P, van Loon H, Owen P, Opie LH. Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism and electrophysiology. J Thorac Cardiovasc Surg 1990;100:445–54.[Abstract]
6. Amrani M, Shirvani R, Allen NJ, Ledingham S, Yacoub MH. Enhancement of low coronary reflow improves postischemic myocardial function. J Thorac Cardiovasc Surg 1992;104:1375–82.[Abstract]
7. Ledingham S, Katayama O, Lachno D, Patel N, Yacoub M. Beneficial effect of adenosine during reperfusion following prolonged cardioplegic arrest. Cardiovasc Res 1990;24:247–53.[Abstract/Free Full Text]
8. Smolenski RT, Lachno DR, Ledingham SJM, Yacoub MH. Determination of sixteen nucleotides, nucleosides and bases using high-performance liquid chromatography and its application to the study of purine metabolism in hearts for transplantation. J Chromatogr 1990;527:414–20.[Medline]
9. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–75.[Free Full Text]
10. Smolenski RT, Suitters A, Yacoub MH. Adenine nucleotide catabolism and adenosine formation in isolated human cardiomyocytes. J Mol Cell Cardiol 1992;24:91–6.[Medline]
11. Smolenski RT, Kochan Z, McDouall R, Seymour A-ML, Yacoub MH. Adenosine uptake and metabolism in human endothelial cells. Adv Exp Med Biol 1995;370:435–8.
12. Smolenski RT, Seymour A-ML, Yacoub MH. Adenosine transport and metabolism in cardiomyocytes of hyperthyroid rat. Adv Exp Med Biol 1995;370:765–8.
13. Smolenski RT, Yacoub MH. Nucleotide metabolism in human cardiomyocytes and endothelium-implications for protection of the heart during cardiac surgery. In: Abd-Elfattah ASA, Wechsler AS, eds. Purines and myocardial protection. Norwell, MA: Kluwer Academic Publishers, 1995:55–80.
14. Dow JW, Bowditch J, Nigdikar SV, Brown AK. Salvage mechanisms for regeneration of adenosine triphosphate in rat cardiac myocytes. Cardiovasc Res 1987;21:188–96.[Medline]
15. Nees S, Herzog V, Becker BF, Bock M, Des Rosiers C, Gerlach E. The coronary endothelium: a highly active metabolic barrier for adenosine. Basic Res Cardiol 1985;80:515–29.[Medline]
16. Ford DA, Rovetto MJ. Rat cardiac adenosine transport and metabolism. Am J Physiol 1987;252:H54–63.[Abstract/Free Full Text]
17. Arch JRS, Newsholme EA. Activities and some properties of 5`-nucleotidase, adenosine kinase and adenosine deaminase in tissues from vertebrates and invertebrates in relation to the control of the concentration and the physiological role of adenosine. Biochem J 1978;174:965–77.[Medline]
18. Visentin S, Wu SN, Belardinelli L. Adenosine-induced changes in atrial action potential: contribution of Ca and K currents. Am J Physiol 1990;258:H1070–8.[Abstract/Free Full Text]
19. Belardinelli L, Isenberg G. Isolated atrial myocytes: adenosine and acetylcholine increase potassium conductance. Am J Physiol 1983;244:H734–7.[Abstract/Free Full Text]
20. Schubert T, Vetter H, Owen P, Reichart B, Opie LH. Adenosine cardioplegia. Adenosine versus potassium cardioplegia: effects on cardiac arrest and postischemic recovery in the isolated rat heart. J Thorac Cardiovasc Surg 1989;98:1057–65.[Abstract]
21. Grover GJ, Sleph PG, Dzwonczyk S. Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors. Circulation 1992;86:1310–6.[Abstract/Free Full Text]
22. Wyatt DA, Ely SW, Lasley RD, et al. Purine-enriched asanguineous cardioplegia retards adenosine triphosphate degradation during ischemia and improves postischemic ventricular function. J Thorac Cardiovasc Surg 1989;97:771–8.[Abstract]
23. Bolling SF, Bies LE, Gallagher KP, Bove EL. Enhanced myocardial protection with adenosine. Ann Thorac Surg 1989;47:809–15.[Abstract]
24. Bolling SF, Bies LE, Bove EL, Gallagher KP. Augmenting intracellular adenosine improves myocardial recovery. J Thorac Cardiovasc Surg 1990;99:469–74.[Abstract]
25. Van der Lee C, Huizer T, Janssen M, et al. Adenosine added to St. Thomas' Hospital cardioplegic solution improves functional recovery and reduces irreversible myocardial damage. Cardioscience 1994;5:269–75.[Medline]
26. Smolenski RT, Lachno DR, Yacoub MH. Adenine nucleotide catabolism in human myocardium during heart and heart-lung transplantation. Eur J Cardiothorac Surg 1992;6:25–30.[Abstract]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Simon J. M. Ledingham Magdi H. Yacoub Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Katayama, O. Articles by Yacoub, M. H. Search for Related Content PubMed PubMed Citation Articles by Katayama, O. Articles by Yacoub, M. H. Related Collections Related Article